The Definition of Primary and Secondary Glioblastoma: Updated Version Author

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The Definition of Primary and Secondary Glioblastoma

Hiroko Ohgaki and Paul Kleihues
Clin Cancer Res Published OnlineFirst December 3, 2012.
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Copyright © 2012 American Association for Cancer Research
Author Manuscript Published OnlineFirst on December 3, 2012; DOI:10.1158/1078-0432.CCR-12-3002
Review
The Definition of Primary and Secondary Glioblastoma
Hiroko Ohgaki1 and Paul Kleihues2
1
International Agency for Research on Cancer, F-69372 Lyon, France, and 2Department of
Pathology, University Hospital Zurich, CH-8091 Zurich, Switzerland
Running title: Definition of primary and secondary glioblastomas
Keywords: primary glioblastoma, secondary glioblastoma, astrocytoma, oligodendroglioma,

IDH1 mutation, TP53 mutation, 1p/19q loss
The authors have no financial support or relationships that may pose a conflict of interest.
Correspondence to:
Dr Hiroko Ohgaki
Molecular Pathology Section
International Agency for Research on Cancer
150 Cours Albert Thomas 69372 Lyon, France
Tel: +33 (0)4 72 73 85 34
Fax: +33 (0)4 72 73 86 98
E-mail: ohgaki@iarc.fr

Abstract
Glioblastoma is the most frequent and malignant brain tumor. The vast majority of
glioblastomas (approximately 90%) develop rapidly de novo in elderly patients, without
clinical or histological evidence of a less malignant precursor lesion (primary
glioblastomas). Secondary glioblastomas progress from low-grade diffuse astrocytoma or
anaplastic astrocytoma. They manifest in younger patients, have a lesser degree of
necrosis, are preferentially located in the frontal lobe and carry a significantly better
prognosis. Histologically, primary and secondary glioblastomas are largely
indistinguishable, but they differ in their genetic and epigenetic profiles. Decisive genetic
signpost of secondary glioblastoma are IDH1 mutations, that are absent in primary
glioblastomas and which are associated with a hypermethylation phenotype. IDH1
mutations are the earliest detectable genetic alteration in precursor low-grade diffuse
astrocytomas and in oligodendrogliomas, indicating that these tumors are derived from
neural precursor cells that differ from those of primary glioblastomas. In this review, we
summarize epidemiological, clinical, histopathological, genetic, and expression features of
primary and secondary glioblastomas, and the biological consequences of IDH1 mutations.
We conclude that this genetic alteration is a definitive diagnostic molecular marker of
secondary glioblastomas and more reliable and objective than clinical criteria. Despite a
similar histological appearance, primary and secondary glioblastomas are distinct tumor
entities that originate from different precursor cells and may require different therapeutic
approaches.
Introduction
Historical perspective
From a biological and clinical point of view, the secondary glioblastomas

developing in astrocytomas must be distinguished from “primary” glioblastomas.
They are probably responsible for most of the glioblastomas of long clinical duration.
H.-J. Scherer (1940) (1).
In a series of publications on gliomas, Hans-Joachim Scherer (1906–1945), a young
German neuropathologist working in exile at the Institut Bunge in Antwerp (Belgium) was
decades ahead of his contemporaries in his insight into the pathology and biology of brain
tumors (2). The distinction between primary and secondary glioblastomas was a
remarkable observation at that time. In the first edition of the World Health Organization
(WHO) Classification of Tumors of the Nervous System, published 40 years later,
glioblastomas were not even recognized as astrocytic neoplasms, but listed in a group of
“poorly differentiated and embryonal tumors” (3). Only after the introduction of
immunohistochemistry was their astrocytic origin unequivocally established (4). Although it

was recognized in clinical practice that some glioblastomas developed after resection of
low-grade or anaplastic astrocytomas, Scherer’s distinction remained conceptual since
histopathologically, these subtypes could not reliably be distinguished.
In 1996, we reported evidence that primary and secondary glioblastomas carry distinct
genetic alterations (5). TP53 mutations were found to be uncommon in primary
glioblastomas, but occurred with a high incidence in secondary glioblastomas; EGFR
overexpression prevailed in primary glioblastomas, but was rare in secondary
glioblastomas. Only 1 out of 49 glioblastomas showed TP53 mutation and EGFR
overexpression, indicating that these alterations are mutually exclusive events defining two
different genetic pathways in the evolution of glioblastoma (5). Subsequently, many studies
provided evidence that primary and secondary glioblastomas develop through distinct
genetic pathways (6,7). Typical for primary glioblastomas are EGFR amplification, PTEN
mutation, and entire loss of chromosome 10 (6-8). Genetic alterations more common in
secondary glioblastomas include TP53 mutations and 19q loss (6,7,9). However, until the
identification of IDH1 mutation as a molecular marker of secondary glioblastoma (10-13),
the patterns of genetic alterations, though different, did not allow an unequivocal separation
of the two subtypes.
IDH1 mutations as initiator and lineage marker in gliomagenesis

IDH1/2 mutations in neural tumors
IDH1 mutations were first reported by Parsons et al. (14) in 2008 and in this first study the
authors already pointed out, that “mutations in IDH1 occurred in a large fraction of young
patients and in most patients with secondary glioblastomas and were associated with an
increase in overall survival’. Subsequent studies showed that these mutations are very
frequent in secondary (>80%), but very rare in primary glioblastomas (<5%) (10-13). IDH1
mutations as a genetic marker of secondary but not primary glioblastoma closely
correspond to the respective clinical diagnosis in 385/407 (95%) of cases (13). It is now
agreed that IDH1 mutation is a definitive diagnostic molecular marker of secondary
glioblastomas and more reliable and objective than clinical and/or pathological criteria.
IDH1 mutations are frequent (>80%) in diffuse astrocytoma WHO grade II and anaplastic
astrocytoma WHO grade III, the precursor lesions of secondary glioblastomas, as well as in
oligodendroglial tumors including oligodendroglioma WHO grade II, anaplastic
oligodendroglioma WHO grade III, oligoastrocytoma WHO grade II, and anaplastic
oligoastrocytoma WHO grade III (10,11,12,15). In contrast, IDH1 mutations are very rare or
absent in pilocytic astrocytomas, as well as in most other CNS neoplasms, including
ependymomas, medulloblastomas, and meningiomas (10,11,12,15). IDH2 mutations are
less frequent and prevail in anaplastic oligodendrogliomas (~5%) and oligoastrocytomas
(~6%) (12).

All IDH1 mutations reported are located at the first or second base of codon 132
(10,11,14). Most frequent is R132H (CGT->CAT), observed in 83–91% of IDH1 mutations
in astrocytic and oligodendroglial gliomas (10-12). Other mutations are rare, including
R132C (CGT->TGT) (3.6–4.6%) (10-12), R132G (0.6–3.8%) (10-12), R132S (0.8–2.5%)
(10-12), and R132L (0.5–4.4%) (10,12). IDH2 mutations are located at codon 172 (12),
with R172K being most frequent.
IDH1/2 mutations in non-neural tumors

IDH1/2 mutations are absent or very rare in most tumors at other organ sites, including
bladder, breast, stomach, colorectum, lung, liver, ovary and prostate (12,15). Exceptions
are central chondrosarcomas (~55%) (16), intrahepatic cholangio-carcinomas (23%) (17),
acute myeloid leukemia (AML; 15–20%) (18-23), angioimmunoblastic T-cell lymphoma
(AITL; ~20%) (24) malignant melanoma (~10%) (25), and anaplastic thyroid cancer (~10%)
(26). This suggests that IDH1/2 mutations may confer a growth advantage in specific cell
lineages at defined stages of development and differentiation.
Are there primary glioblastomas with IDH1 mutations?

In a population-based study, only 14 of 407 glioblastomas clinically diagnosed as primary
(3.4%) carried an IDH1 mutation (13). These patients were 10 years younger and their
genetic profiles were similar to those of secondary glioblastomas, including frequent TP53
mutations and absence of EGFR amplification (13). Similarly, several hospital-based
studies showed that primary glioblastomas with IDH1 mutations were 13-27 years younger
than those without IDH1 mutations (10,12,27,28). Toedt et al. (27) showed that primary
glioblastomas with IDH1 mutations have gene expression profiles similar to those of IDH1
mutated secondary glioblastomas. Glioblastomas with IDH1 mutations clinically diagnosed
as primary may have rapidly progressed from precursor lesions that escaped clinical
diagnosis and are likely to have been misclassified as primary glioblastoma.
Are there secondary glioblastomas that do not have IDH1 mutations?

Secondary glioblastomas lacking IDH1 mutations have infrequent TP53 mutations, and
patients have a shorter clinical history (13). Furthermore, most secondary glioblastomas
lacking IDH1 mutations (7/8) had developed through progression from an anaplastic glioma
(WHO grade III), whereas the majority of secondary glioblastomas with IDH1 mutations
had progressed from a WHO grade II glioma (13). The possibility therefore exists that
some tumors diagnosed as anaplastic astrocytoma were actually primary glioblastomas
that were misdiagnosed due to a sampling error. In the absence of diagnostic hallmarks,
i.e. necrosis and/or microvascular proliferation pathologists hesitate to make a diagnosis of
glioblastoma even if MRI imaging suggests this.

Timing of IDH1/2 mutations in the pathway to secondary glioblastoma

IDH1/2 mutations are an early event in gliomagenesis and persist during progression to
secondary glioblastoma. In addition to frequent IDH1/2 mutations, about 60% of diffuse
astrocytomas carry a TP53 mutation, while oligodendrogliomas show frequent 1p/19q loss
(~70%) (11,29-33). IDH1/2 mutations is likely to occur before TP53 mutation or 1p/19q
loss, since low-grade diffuse gliomas carrying only IDH1/2 mutations are more frequent
(17%) than those carrying only a TP53 mutation (2%) or those showing only 1p/19q loss
(3%) (33). Furthermore, the analysis of multiple biopsies from the same patient revealed
that there was no cases in which an IDH1 mutation occurred after the acquisition of a TP53
mutation or loss of 1p/19q (11,33).
Acquisition of 1p/19q loss in cells with IDH1/2 mutations may be the driving force
towards oligodendroglial differentiation in low-grade diffuse glioma (11,31,33). It has been
shown that tumors with the typical histological signature of oligodendroglioma (e.g.
honeycomb appearance of most neoplastic cells) showed loss at 1p/19q in the vast
majority of cases (> 90%) (31). Furthermore, exomic sequencing recently revealed that
mutations in the CIC gene (homologue of the Drosophila gene capicua) at 19q13.2 and in
the FUBP1 gene at 1p are frequent in oligodendrogliomas, but rare or absent in diffuse
astrocytomas (34-36).
Astrocytomas typically develop in cells with IDH1/2 mutations that subsequently acquire
TP53 mutations. Recent studies have also described mutations in the ATRX (α-
thalassemia/mental-retardation-syndrome-X-linked) gene that are often co-present with
IDH1/2 mutations and TP53 mutations in diffuse astrocytomas WHO grades II/III and
secondary glioblastomas (36,37). Our current concept of the genetic pathways leading to
astrocytic and oligodendroglial gliomas is summarized in Fig. 1.
Only 7% of WHO grade II diffuse gliomas had none of these genetic alterations (i.e.
IDH1/2 mutations, TP53 mutations, 1p/19q loss) and were termed “triple negative” (33).
These cases are still poorly understood; a minor fraction shows loss of cell cycle control
regulated by the RB1 pathway (38). The possibility cannot be excluded that they are
derived from a different precursor cell population.
IDH1 mutations in gliomas associated with the Li-Fraumeni syndrome

As indicated above, IDH1 mutations precede TP53 mutations in sporadic astrocytic tumors.
Patients with Li-Fraumeni syndrome (LFS) carry a germline TP53 mutation that is present
in every somatic cell. Thus, by definition TP53 mutations would be the first event in LFS-
associated gliomas which account for 12–13% of all tumors occurring in LFS families
(39,40). In patients from three families with LFS, we identified IDH1 mutations in five
astrocytic gliomas that developed in carriers of a TP53 germline mutation. Without

exception, all contained the R132C (CGT>TGT) mutation (41), which in sporadic astrocytic
tumours amounts to less than 5% of all IDH1 mutations (10-12). This remarkably selective
occurrence suggests a preference for R132C mutations in neural precursor cells that
already carry a germline TP53 mutation.
Biological consequences of IDH mutations

The mechanisms by which IDH1 mutations contribute to the development and malignant
progression of astrocytic and oligodendroglial tumors are still not fully understood.
Conditional IDH1 (R132H) knock-in mice with expression in all hematopoietic cells or cells
of the myeloid lineage caused an increased number of early hematopoietic progenitors with
splenomegaly, anemia and extramedullary hematopoiesis (42), while brain-specific IDH1
(R132H) conditional knock-in mice exhibited hemorrhage and perinatal lethality (43). Like
EGFR amplification in primary glioblastomas, IDH1 mutations in secondary glioblastomas
are typically lost during culture in vitro (44). This is enigmatic, since selective suppression
of endogenous mutant IDH1 expression in a fibrosarcoma cell line with a native
IDH1R132C heterozygous mutation, significantly inhibits cell proliferation (45). Only
recently, using a neurosphere culture method, it has been possible to establish a brain
tumor stem cell line from an IDH1-mutant anaplastic oligoastrocytoma with an endogenous
IDH1 mutation and detectable production of 2-hydroxyglutarate (2HG) (46). This may
suggest that IDH1-mutant glioma cells have stem-cell-like features that confer a growth
advantage under neurosphere culture conditions. Alternatively, there may be intra-tumoral
heterogeneity of IDH1 mutations, and neoplastic cells lacking IDH1 mutations are positively
selected during culture.
Impaired enzymatic activity and accumulation of 2-hydroxyglutarate

The IDH1 gene encodes isocitrate dehydrogenase 1, an enzyme participating in the citric
acid (Krebs) cycle (47,48), the metabolic pathway used by aerobic organisms to generate
usable energy (49). IDH1/2 mutations reduce the wild-type activity of the enzyme, i.e. the
conversion of isocitrate to α-ketoglutarate (α-KG), and increase levels of hypoxia inducible
factor-1α (HIF-1α), a transcription factor, and its targets (e.g. GLUT1, VEGF and PGK1)
(50). Importantly, IDH1/2 mutations are gain-of-function mutations that also produce the
oncometabolite 2HG from α-KG (51,52). The production of 2HG is a function shared by all
the commonly occurring IDH1/2 mutants analyzed (51-53). Malignant IDH1mut gliomas
contain an increased (up to 100-fold) concentration of 2HG (51). Cells from brain-specific
IDH1 (R132H) conditional knock-in mice also show high levels of 2HG that are associated
with inhibited prolyl-hydroxylation of HIF-1α and upregulation of its target genes (43). 2HG
also blocks prolyl-hydroxylation of collagen, causing a defect in collagen protein

maturation, leading to basement-membrane aberrations that may play a role in glioma

progression (43).
Hypermethylation phenotype
Noushmehr et al. (54) first reported that IDH1/2mut glioblastomas displayed concerted CpG
island methylation at a large number of loci. A similar hypermethylation phenotype was
also observed in IDH1/2mut diffuse astrocytomas (55) and oligodendroglial tumors (55), as
well as in IDH1/2mut AML (56). Turcon et al. (57) introduced mutant IDH1 into primary
human astrocytes, causing alteration of specific histone markers and induction of extensive
DNA hypermethylation, suggesting that the presence of an IDH1 mutation is sufficient to
establish a hypermethylation phenotype in glioma. This is supported by the observation
that the expression of IDH1 (R132H) in cells of myeloid lineage in knock-in mice resulted in
hypermethylated histones and changes in DNA methylation similar to those observed in
human IDH1/2mut AML (42). Stable transfection of a 2HG-producing IDH mutant into
immortalized astrocytes resulted in progressive accumulation of histone methylation which
was associated with repression of the inducible expression of lineage-specific
differentiation genes and a block to differentiation, suggesting that 2HG producing IDH1/2
mutants can prevent the histone demethylation that is required for lineage-specific
progenitor cells to differentiate into terminally differentiated cells (58). Duncan et al. (59)
knocked-in a single copy of the IDH1 R132H into a human cancer cell line and profiled
changes in DNA methylation at > 27,000 CpG dinucleotides. Heterozygous expression of
mutant IDH1 was sufficient to induce widespread alterations in DNA methylation, including
hypermethylation of 2,010 and hypomethylation of 842 CpG loci, many of which were
consistent with those observed in IDH1-mutant and G-CIMP+ primary gliomas (59).
IDH1 mutations and the proneural signature of glioblastomas

Glioblastomas have been classified on the basis of cDNA expression profiles, with distinct
proneural, neural, classic, mesenchymal, and proliferative patterns (60,61). Most IDH1mut
glioblastomas (11/12, 92%) show a proneural expression signature; conversely,
approximately 30% of glioblastomas with a proneural signature are IDH1mut (61).
Glioblastomas lacking IDH1 mutations have all been identified as classical, mesenchymal,
neural or proneural (61).
These observations suggest that secondary glioblastomas are a rather homogeneous
group of tumors characterized by a proneural expression pattern, whereas primary
glioblastomas are heterogeneous, with several distinct expression profiles. Diffuse
astrocytomas, oligodendrogliomas and oligoastrocytomas all show the typical proneural
signatures (62), again supporting the view that these neoplasms share common neural
progenitor cells.

Incidence of secondary glioblastomas

Until the discovery of IDH1 mutations as a molecular marker, the distinction between
primary and secondary glioblastomas was based on clinical observations. Tumors were
considered primary if the diagnosis of glioblastoma was made at the first biopsy, without
radiological or histological evidence of a pre-existing, less malignant precursor lesion. The
diagnosis of secondary glioblastoma required neuro-imaging and/or histological evidence
of a preceding low-grade or anaplastic astrocytoma (6,7).
In developed countries, the annual incidence of glioblastomas is usually in the range of
3–4 cases per 100’000 persons per year (7,63-65). In a population-based study in
Switzerland, using clinical criteria and histopathological evidence, only 5% of all
glioblastomas diagnosed were secondary (7,63). Similarly, a study by the University of
Alabama showed that 19 of 392 (5%) cases of glioblastoma had a histologically proven
prior low-grade glioma (66). When IDH1 mutations are used as a genetic marker,
secondary glioblastomas accounted for 9% of all glioblastomas at the population level (13)
and for 6–13% in hospital-based studies (10,12,67,68).
The combined incidence rates of low-grade and anaplastic astrocytomas are
approximately twice as high as that of clinically diagnosed secondary glioblastoma or
IDH1mut glioblastoma (30,64,69). This may be explained at least in part by the fact that
some patients with low-grade or anaplastic astrocytoma succumb to the disease before
progression to glioblastoma occurs. Further, cases with rapid progression from low-grade
or anaplastic astrocytoma may be misclassified as primary glioblastoma.
Age and sex distribution

There is a striking difference in the age distribution of patients with primary and secondary
glioblastoma. At a population level, the mean age of glioblastoma patients clinically
diagnosed as primary was 62 years, while secondary glioblastomas developed in younger
patients (mean, 45 years) (7,63). Similarly, the mean ages of patients with or without IDH1
mutations were 61 and 48 years, respectively (Table 1) (13). Several hospital-based
studies showed that patients with IDH1mut glioblastoma are significantly younger (mean
age, 32-41 years) than those without IDH1 mutations (mean age, 56–59 years) (12,67,70).
Glioblastomas predominantly affect males, with a population-based M/F ratio ranging
from 1.28 (7) to 1.32 (64,65). In contrast, diffuse astrocytomas (WHO grade II) have a less
pronounced male predominance, with M/F ratios of approximately 1.17 (29,65). Since
secondary glioblastomas typically develop from diffuse astrocytomas, one would expect
that they have a similar gender ratio. This is indeed the case. In a population–based study,
IDH1mut secondary glioblastomas had an M/F ratio of 1.12, significantly lower than the ratio
of 1.46 in primary glioblastoma patients (7). Several hospital-based studies also showed a

tendency towards a lower M/F ratio of patients with secondary glioblastomas (5,71-74). In a
recent multi-center study, 49 of 618 glioblastomas (7.9%) carried an IDH1 mutation and
had an M/F ratio of 0.96, in contrast to a ratio of 1.63 for non-mutated (primary)
glioblastomas (68).
Clinical history
At a population level, the majority of patients with primary glioblastoma (68%) had a clinical
history of less than 3 months (6). The mean duration of the clinical history of patients with
primary and secondary glioblastoma was 6.3 and 16.8 months, respectively (7,63).
Similarly, patients with glioblastomas lacking IDH1 mutations had a mean duration of
preceding clinical symptoms of 3.9 months, significantly shorter than patients with IDH1mut
glioblastoma (mean, 15.2 months; P=0.0003) (13). Glioblastomas clinically diagnosed as
primary had a mean clinical history of about 4 (IDHwt) and 29 months (IDHmut), respectively
(13). It remains to be analyzed why the precursor lesions of these IDHmut secondary
glioblastomas escaped clinical detection despite their long clinical history.
Localization
Lai et al. (68) reported that glioblastomas lacking IDH1 mutations show widespread
anatomical distribution, whereas IDH1mut glioblastomas have a striking predominance of
frontal lobe involvement, in particular in the region surrounding the rostral extension of the
lateral ventricles. Stockhammer et al. (75) showed that IDH1/2mut WHO grade II
astrocytomas tend to develop in a frontal location, and that seizures were the initial
symptom in approx. 70% of patients. According to Zlantescu et al. (76) oligodendroglial
tumors with 1p/19q losses occur most frequently in the frontal lobe and have a tendency for
widespread growth across the midline. Similarly, Laigle-Donadey et al. (77) showed that
oligodendrogliomas with 1p/19q loss were located predominantly in the frontal lobe. These
observations suggest that oligodendrogliomas, astrocytomas, and secondary glioblastomas
derived thereof originate from precursor cells located in or migrating to, the frontal lobe.
Extent of necrosis
Already in his 1940 publication, Scherer noted that “the absence of extensive necrosis and
peritumoral brain swelling in secondary and their almost constant presence in primary
glioblastomas may play a certain role in the clinical behaviour of the two types” (1). He
attributed this to the slower growth rate of secondary glioblastomas. It is now understood
that an hypoxia-mediated activation of the coagulation system causes intravascular
thrombosis, further increases intratumoral hypoxia and leads to abnormal endothelial cell
proliferation and tumor necrosis (78,79). Microvascular proliferation is induced by VEGF,

10
which shows a markedly higher expression in primary than in secondary glioblastomas

(71).
Histopathologically, large areas of ischemic and/or pseudopalisading necrosis are more
frequent in primary (89%) than secondary glioblastomas (63%, P=0.0014) (80) and
glioblastomas without IDH1 mutations (90% vs. 50%; P<0.0001) (13) (Table 1). This was
confirmed in clinical MRI studies showing that necrosis was less frequent in IDH1mut
glioblastomas while exhibiting more frequent non-enhancing tumor components, larger size
at diagnosis, lesser extent of edema, and increased prevalence of cystic and diffuse
components (68).
Histological features
According to the 2007 WHO classification, histological criteria for the diagnosis of
glioblastoma include nuclear atypia, cellular pleomorphism, mitotic activity, vascular
thrombosis, microvascular proliferation, and necrosis (29). Glioblastomas may show
significant intertumoral and intratumoral heterogeneity, both histologically and genetically
(80-82) and this may also apply to glioma initiating cells (82,83). This heterogeneity reflects
genomic instability and occasionally, focal new clones arising as a result of additional
genetic alterations can be seen histologically (84,85). Areas with oligodendroglioma-like
components are significantly more frequent in secondary than primary glioblastomas (42%
vs. 18%, P=0.0138) (80) and, accordingly, more frequent in IDH1mut glioblastomas than in
IDH1wt glioblastomas (54% vs. 20%; P<0.0001) (13) (Table 1). An increase in the fraction
of tumor cells with oligodendroglial morphology in IDH1mut glioblastomas was also reported
in a large study of 618 cases (68). This is not surprising since secondary glioblastomas
assumedly share IDH1mut precursor cells with oligodendrogliomas (Fig. 1).
Clinical outcome
In a population-based study, the median overall survival of clinically diagnosed secondary
glioblastoma was 7.8 months, significantly longer than the survival of patients with primary
glioblastoma (4.7 months; P=0.003) (7). Similarly, the analysis of glioblastoma patients
who were treated with surgery and radiotherapy showed that the mean overall survival time
of patients with IDH1mut glioblastoma was 27.1 months, more than twice as long as that of
patients with IDH1wt glioblastoma (11.3 months; P<0.0001) (13). Yan et al. (12) reported
that IDH1mut glioblastomas treated with radio/chemotherapy had an overall survival time of
31 months, again twice as long as IDH1wt tumours. A different response to therapy is also
supported by the observation that dose enhancement did not improve the outcome of
glioblastomas with a proneural signature (containing IDH1mut cases), in contrast to
glioblastomas with neural, classical or mesenchymal signature, which all profited from

11
more intensive therapy (61). If confirmed in prospective clinical trials, this may eventually
allow for dose de-escalation in patients with secondary glioblastoma.
Origin of primary and secondary glioblastomas

Before the discovery of IDH1 mutations as a lineage marker, it was assumed that primary
and secondary glioblastomas developed from the same precursor cell population, but show
distinct clinical and biologic behavior due to the acquisition of different genetic alterations
(6). There is now increasing evidence that, despite their similar histological features,
primary and secondary glioblastomas develop from different cells of origin. The evidence
supporting this hypothesis includes the observations that: (i) only secondary glioblastomas
but not primary glioblastomas share common IDH1/2 mutations with oligodendrogliomas;
(ii) primary and secondary glioblastomas develop in patients of different age groups and
have a different sex distribution; (iii) primary and secondary glioblastomas are located in
different brain regions; and (iv) primary and secondary glioblastomas have a significantly
different clinical outcome. All these data indicate that primary and secondary glioblastomas
are in fact different tumor entities that are derived from distinctly different neural precursor
cells.
There is also evidence that cancer stem cells in primary and secondary glioblastomas
may also be different. In one study, the relative content of CD133+ cells was significantly
higher in primary than in secondary glioblastomas, and CD133+ expression was
associated with neurosphere formation only in primary, but not secondary glioblastomas
(86).
Phenotype / genotype correlations

Despite differences in clinical history and genetic, epigenetic and expression profiles,
primary and secondary glioblastomas are histologically largely indistinguishable, except
that extensive necrosis is more frequent in primary glioblastomas and oligodendroglioma
components are more frequent in secondary glioblastomas (80) (Table 1). This similarity
may be attributable to genetic alterations that are common to both primary and secondary
glioblastomas.
The most frequent genetic alteration shared by both primary and secondary
glioblastomas is LOH at 10q (up to 60% of cases) (6-8,87-89), the most commonly deleted
region being 10q25-qter, distal to D10S1683 (8). Since mutations of the PTEN gene
located at 10q23.3 prevail in primary glioblastomas (~25%), but are rare in secondary
glioblastomas (<5%) (6,7,90), loss of function of gene(s) other than PTEN is likely to be
responsible for the common malignant phenotype. Circumscribed glioblastoma foci in low-
grade diffuse astrocytoma or anaplastic astrocytoma show additional deletions at 10q25-
qter, distal to D10S597, including the DMBT1 and FGFR2 loci (84). This suggests that the

12
acquisition of a highly malignant glioblastoma phenotype is associated with loss of putative

tumor suppressor gene(s) on 10q25-qter.
Pace of malignant progression to secondary glioblastoma

The ability to predict the pace of progression from low-grade diffuse astrocytoma to
secondary glioblastoma would be clinically very important by giving oncologists a rational
basis for deciding whether and at which stage to administer adjuvant radiotherapy.
Histopathologically, this is not possible, as Scherer noted already in 1940: “Why certain
astrocytomas become transformed into glioblastomas while others remain pure, is still
obscure. No morphological sign explaining or announcing this tendency could be found”
(1).
When commonly deleted genes at 10q25-qter in IDHwt and IDHmut glioblastomas were
searched for in The Cancer Genome Atlas (TCGA) (91), 10 genes were identified with log-
ratio thresholds of –1.0, and of these, DMBT1 at 10q26.13 was the only homozygously
deleted gene in glioblastomas with or without IDH1 mutations (12.5% vs. 8.0%) (92).
DMBT1 homozygous deletion was detected at a similar frequency in an independent set of
primary and secondary glioblastomas (20% vs. 21%) (92). A small fraction (11.3%) of
diffuse astrocytomas WHO grade II also showed a DMBT1 homozygous deletion, and this
was significantly associated with shorter overall patient survival (92). A similar approach
was used to search for commonly amplified genes in IDHwt and IDHmut glioblastomas in the
TCGA database. A total of 25 genes were identified, of which 21 were located at 7q31-34
(93). Further analyses revealed gain of the MET gene at 7q31.2 in primary glioblastomas
(47%) and secondary glioblastomas (44%). Interestingly, MET gain is also common in
diffuse astrocytomas (38%), and was associated with shorter survival (93). These results
indicate that several genetic alterations frequent in both primary and secondary
glioblastomas may be responsible for the common histological phenotype and, if already
present in diffuse astrocytomas, may predict unfavorable clinical outcome (92,93). Whole-
genome DNA sequencing of diffuse astrocytomas (WHO grade II) and anaplastic
astrocytomas (WHO grade III) in patients with favorable or poor outcome is likely to identify
further genetic alterations that drive the malignant progression to secondary glioblastoma.

13
Figure legend
Fig. 1
Genetic pathways to primary and secondary glioblastomas. Note that only secondary
glioblastomas share common origin of cells with oligodendrogliomas.

14
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Table 1 Primary and secondary glioblastomas: Comparison of clinical vs. genetic diagnosis
Primary glioblastoma Secondary glioblastoma Refs

wt mut
Clinical criteria* IDH1 Clinical criteria* IDH1
Fraction in a population 94.7% 91.2% 5.3% 8.8% (7,13)
Mean age 59-62 years 56-61 years 33-45 years 32-48 years (7,12,13,67,70)
Male/female ratio 1.33-1.5 1.2-1.46 0.65-2.3 1.0-1.12 (7,12,13,70)
Mean clinical history 6.3 months 3.9 months 16.8 months 15.2 months (7,13)
Median overall survival (7,12,13)

Surgery / radiotherapy 4.7 months** 9.9 months 7.8 months** 24 months (7,13)
+ radio/chemotherapy 15 months 31 months (12)
Histologic features
Oligodendroglial 18% 20% 42% 54% (13,80)
comp.
Necrosis 89% 90% 63% 50% (13,80)
Genetic alterations
IDH1 mutations 4-7% 0%* 73-88% 100%* (10,12,13)
TP53 mutations 17-35% 19-27% 60-88% 76-81% (7,10,12,13,67,91)
ATRX mutations 4-7% 57-80% (36,37)
EGFR amplification 36-45% 35-39% 0-8% 0-6.5% (7,10,12,13,91)
CDKN2A deletion 31-52% 30-45% 19-20% 7-22% (7,12,13,91)
PTEN mutations 23-25% 24-26% 4-12% 0-% (7,12,13)
19q loss 6% 4% 54% 32% (9,13)
1p/19q loss 2-8% 0-13% (10,12,67)
10p loss 47% 8% (8)
10q loss 70% 67% 63% 73% (7,13)
* Tumors were considered to be primary if the diagnosis of glioblastoma was made at the first biopsy, without clinical or histological evidence of a
pre-existing, less malignant precursor lesion, whereas the diagnosis of secondary glioblastoma required histological and/or clinical (neuro-
imaging) evidence of a preceding low-grade or anaplastic astrocytoma.
** Data from population-based study: all the patients who were treated in different ways were included.
Figure 1:
Glial progenitor cells Glial progenitor cells
Common precursor cells with IDH1/2 mutation
TP53 mutation (~65%) Loss 1p/19q (>75%) WHO

ATRX mutation (~65%) CIC mutation (~40%)
grade
3–6 months FUBP1 mutation (~15%)
clinical history
Diffuse astrocytoma Oligodendroglioma II
~5 yrs
EGFR amplification (~35%)
Anaplastic Anaplastic
TP53 mutation (~30%) III
PTEN mutation (~25%) astrocytoma oligodendroglioma
LOH 10p (~50%)
LOH 10q (~70%) LOH 19q (~50%)
LOH 10q (>60%) ~2 yrs
Primary Secondary
IV
glioblastoma glioblastoma
Neural, classical, mesenchymal, Proneural transcriptional profile

proneural transcriptional profiles Hypermethylation phenotype
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Author Manuscript Published OnlineFirst on December 3, 2012; DOI:10.1158/1078-0432.

The Definition of Primary and Secondary Glioblastoma

Clin Cancer Res Published OnlineFirst December 3, 2012.

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Hiroko Ohgaki1 and Paul Kleihues2

Running title: Definition of primary and secondary glioblastomas

Keywords: primary glioblastoma, secondary glioblastoma, astrocytoma, oligodendroglioma,

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From a biological and clinical point of view, the secondary glioblastomas

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IDH1 mutations as initiator and lineage marker in gliomagenesis

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IDH1/2 mutations in non-neural tumors

Are there primary glioblastomas with IDH1 mutations?

Are there secondary glioblastomas that do not have IDH1 mutations?

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Timing of IDH1/2 mutations in the pathway to secondary glioblastoma

IDH1 mutations in gliomas associated with the Li-Fraumeni syndrome

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Biological consequences of IDH mutations

Impaired enzymatic activity and accumulation of 2-hydroxyglutarate

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maturation, leading to basement-membrane aberrations that may play a role in glioma

IDH1 mutations and the proneural signature of glioblastomas

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Incidence of secondary glioblastomas

Age and sex distribution

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which shows a markedly higher expression in primary than in secondary glioblastomas

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Origin of primary and secondary glioblastomas

Phenotype / genotype correlations

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acquisition of a highly malignant glioblastoma phenotype is associated with loss of putative

Pace of malignant progression to secondary glioblastoma

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1. Scherer HJ. Cerebral astrocytomas and their derivatives. Am J Cancer 1940;40:159-

2. Peiffer J,.Kleihues P. Hans-Joachim Scherer (1906-1945), pioneer in glioma

4. Kleihues P, Burger PC, Scheithauer BW. Histological Typing of Tumours of the

5. Watanabe K, Tachibana O, Sato K, Yonekawa Y, Kleihues P, Ohgaki H.

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